Chapter 8. Substitution reactions of Alkyl Halides There are two types of possible reaction in organic compounds in which sp 3 carbon is bonded to an electronegative atom or group (ex, halides) 1. Substitution reactions: electronegative group (leaving group) is substituted by another atom or group (nucleophile). 2. Elimination reactions: electronegative group is eliminated along with a hydrogen atom from an adjacent carbon. *** How Alkyl Halides React The sp 3 carbon will be charged positively because the strong electronegative atom will withdraw electrons from a sp 3 carbon. Since there is an unequal electron distribution in alkyl halides, substitution and elimination reactions are possible in those. Two possible substitution reactions: 1. S N 2: as a nucleophile approaches to the positively charged carbon(forms a new σbond), the halogen atom leaves from the carbon (breaks carbon-halogen bond) 2. S N 1: The carbon-halogen bond breaks heterolytically to form a carbocation, and then a nucleophile reacts with the carbocation intermediate.
Nucleophilic substitution reaction mechanism depends on the followings: 1. The structure of the alkyl halides 2. The reactivity and structure of the nucleophile 3. The concentration of the nucleophile 4. The solvent 8.1 The Mechanism of S N 2 Reaction The mechanism of a reaction is determined by the factors that affect the rate of the reaction. The rate law tells us what molecules are involved in the transition state of the ratedetermining step of the reaction. Experimental evidence for S N 2 reaction: 1. The rate of the reaction depends on the concentration of the alkyl halide and on the concentration of the nucleophile, which means both alkyl halide and nucleophile are involved in the transition state. Rate = k[alkyl halide][nucleophile], so it is a second order reaction. 2. As the alkyl halide has more substituents on the carbon, the rate undergoes slowly. 3. The configuration of the product is the opposite of the reactant => back side attack. The mechanism of S N 2 reaction: 1. As a nucleophile approaches to the positively charged carbon from the opposite side of the leaving group (back side attack), the halogen atom leaves from the carbon. The nonbonding electrons of a nucleophile interacts with the empty σ* molecular orbital.
2. Since the nucleophile attacks the back side of the carbon, which is bonded to the halogen, bulky substituents will make it harder for the nucleophile to attack the carbon. So the rate of reaction decreases. And this is called steric effect. 3. As the nucleophile approaches the back side of the carbon, the carbon-hydrogen bonds begin to move away from the nucleophile. In the transition state, the carbon-hydrogen bonds are all in the same plane. Inversion of configuration: the product gets the opposite configuration of the reactant. Retention of configuration: the product gets the same configuration of the reactant. 8.2 Factors That Affect S N 2 reactions 1) The Leaving group The weaker the basicity of a group, the better its leaving ability: I - > Br - > Cl - > F - 1. A weak base does not share its electrons as well as a strong base does. So a weak base is not bonded to the carbon. 2. In the transition state, some negative charge is transferred to the leaving group. Thus, stabilizing the charge of the anion increases the rate of the reaction. The stability of anion is inversely related to their basicity. 2) The Nucleophile Basicity is a measure of how strongly the base shares electrons with a proton, and it is measured by an acid dissociation constant (K a ). Nucleophilicity is a measure of how readily the nucleophile is able to attack an electrondeficient atom, and it is measured by a rate constant (k). In molecules with the same attacking atom, there is generally a direct relationship between basicity and nucleophilicity: stronger bases are better nucleophiles. In molecules with attacking atoms of approximately the same size, there is generally a direct relationship between basicity and nucleophilicity: - CH 3 > - NH 2 > HO - > F - In molecules with attacking atoms that are very different in size, there is generally a direct relationship between basicity and nucleophilicity only in gas phase. In liquid phase, the relationship between nucleophilicity and basicity depends on the solvent. 1. If the solvent is polar aprotic solvent which does not have protons for hydrogen bonding to nucleophile (ex, DMF, DMSO, Acetonitrile), there is a direct relationship.
2. If the solvent is protic, the relationship between basicity and nucleophilicity becomes inverted. 3. Protic solvents have positively charged hydrogen, which can cause ion-dipole interaction with a nucleophile. Therefore, the nucleophile needs to break the ion-dipole interaction to act as a good nucleophile. So, weaker bases are better nucleophiles. An S N 2 reaction proceeds in the direction that allows the stronger base to displace the weaker base. If the difference between the basicities of the nucleophile and the leaving group is not very large, the reaction may be reversible. The structure of the substrate is also important in S N 2 reactions: the reaction rate of the S N 2 reaction is faster in less hindered carbon: methyl > primary > secondary > tertiary (relative rate, S N 2) 3) Nucleophilicity Is affected by Steric Effects A bulky nucleophile cannot approach the back side of a carbon as easily as a less sterically hindred nucleophile can. 8.3 The Reversibility of an S N 2 Reaction Depends on the Basicities of the the Leaving Groups in the Forward and Reverse Directions An S N 2 reaction proceeds in the direction that allows the stronger base to displace the
weaker base(the better leaving group). If the difference between the basicities of the nucleophile and the leaving group is not very large, the reaction will be reversible. A reversible reaction can be completed by removing one of the products. 8.4 The Mechanism of an S N 1 Reactions Experimental results for the S N 1 reaction: 1. According to the kinetic experiment, the rate of the reaction depends only on the concentration of alkyl halide, which means that the rate-determining transition state contains only the alkyl halide (unimolecular). 2. Less hindered alkyl halides show slow rate of S N 1 reaction. 3. The product of S N 1 reaction is a mixture of two stereoisomers: retention and inversion. The mechanism of S N 1 reaction 1. In the first step, the carbon-halogen bond breaks heterolytically to form carbocation. 2. In the second step, the nucleophile reacts with the carbocation. 3. The first step is the slow and rate-determining step, so the concentration of the nucleophile does not affect the rate of S N 1 reaction. Explanation of the experimental results is based on the mechanism 1. Since the alkyl halide is the only species that participates in rate-determining step, it is a first order reaction (unimolecular). 2. In the first step, a carbocation is formed. Because a tertiary carbocation is more stable than a secondary carbocation, highly substituted (ex, tertiary) alkyl halides undergoes S N 1 reaction faster than less substituted alkyl halides. 3. The intermediate, carbocation, is sp 2 hybridized, and the structure of the intermediate is a planar. So the nucleophile can attack the carbocation from either side of the plane to form two stereoisomers.
Because the first step is the rate-determining step, two factors affect the rate of an S N 1 reaction: leaving group and the stability of carbocation. 1. Tertiary alkyl halide > secondary > primary > methyl 2. The weaker the base is, the easier it is to break the carbon-halogen bond. The nucleophile has no effect on the rate of the S N 1 reaction. Sometimes, the solvent is the nucleophile, and this kind of reaction is called solvolysis reaction. The carbocation is an intermediate in S N 1 reaction, and the carbocation can rearrange to get the more stable carbocation. Therefore, S N 1 and S N 2 reaction can produce different constitutional isomers, because the carbocation is not involved in S N 2 reaction. 8.5 Factors That Affects S N 1 Reactions The leaving group: 1. The ease with which the leaving group dissociates from the carbon 2. The stability of the carbocation that is formed. 3. The weaker the base, the less tightly it is bonded to the carbon and more easily the carbonhalogen bond can be broken. The Nucleophile 1. Rate determinig step in S N 1 is the formation of carbocation. 2. The nucleophile participates in the second step, the nucloephile has no effect on the rate of S N 1 reaction. Carbocation Rearrangement 1. The carbocation which is formed in the first step can go through rearrangement if the more stable carbocation is possible.
8.6 More About the Stereochemistry of S N 1 and S N 2 Reactions Reaction type S N 2 S N 1 products inversion inversion and retention In general, 50 to 70% of the product of an S N 1 reaction is the inverted product: partial racemization. Saul Winstein s explanation: 1. Intimate ion pair: the bond between the carbon and the leaving has broken but the cation and anion remain next to each other. 2. Solvent separated ion pair: the cation and the anion are separated by solvent. 3. Dissociated ion: two totally separated cation and anion. 4. If the nucleophile attacks only the completely dissociated carbocation, the product will be completely racemic. 5. If the nucleophile attacks the carbocation of either the intimate ion pair or the solventseparated ion pair, the leaving group will be in position to partially block the approach of the nucleophile to that side of the carbocation, which leads to the inverted product. 6. In cyclic compounds, it is much easier to see. 8.7 Benzylic Halides, Allylic Halides, Vinylic halides, and Aryl Halies Benzylic and allylic halides readily undergo S N 2 reaction unless they are tertiary, tertiary halides are unreactive because of the steric hindrance. Benzylic and allylic halides undergo S N 1 reaction because of the stability of the carbocation. The intermediate, carbocation, is stabilized by resonance.
Vinylic halides and aryl halides can not undergo an S N 2 reaction because the electron rich nucleophile is repelled by the πelectron cloud of the double bond or the aromatic ring. They can not undergo an S N 1 reaction because of the following reasons: 1. Vinylic and aryl cations are less stable than even primary carbocations. 2. sp 2 carbons form stronger bonds than do sp 3 carbon. 8.8 Competition between S N 2 and S N 1 Reaction Comparison of the S N 2 and S N 1 reactions Sometimes, both S N 1 and S N 1 reaction compete => What is the condition for an S N 1 reaction? Factors to determine which reaction will be predominant, S N 2 or S N 1? 1. The concentration of the nucleophile 2. The reactivity of the nucleophile 3. The solvent An S N 2 reaction is favored by a high concentration of a good nucleophile. An S N 1 reaction is favored by a low concentration of a good nucleophile or a poor nucleophile. Rate = k 2 [alkyl halide][nucleophile] + k 1 [alkyl halide] 1. Increase of the concentration of the nucleophile will affect the first term, which is the contribution to the rate by an S N 2 reaction. 2. Increase the reactivity of the nucleophile has no effect on the rate of an S N 1 reaction. 8.9 The Role of the Solvent in S N 2 and S N 1 Reactions Dielectric constant: measure of how well the solvent can insulate opposite charges from one another by solvation.
Therefore, polar solvents have high dielectric constants. An S N 1 reaction occurs readily in polar solvent: An S N 1 reaction contains the breakage of the carbon-halogen bond to form a carbocation. And the carbocation will be stabilized by polar solvents (ion-dipole interaction). The effect of the solvent on the rate of a reaction: 1. In general, the charge is stabilized by solvent molecules. 2. If the charge on the reactant is greater than the charge on the rate-determining transition state, a polar solvent will interact more strongly with the reactant, so the activation energy will be bigger. Therefore, the polar solvent will decrease the rate of the reaction. => This is the case of charged nucleophile in an S N 2 reaction (Figure 8.8). 3. If the charge on the rate-determining transition state is greater than the charge on the reactant, a polar solvent will interact more strongly with the transition state, so the activation energy will be smaller. Therefore, the polar solvent will increase the rate of the reaction (Figure 8.9). => This is the case of an S N 1 reaction and an S N 2 with a neutral nucleophile. An S N 2 reaction with a negatively charged nucleophile occurs readily in a nonpolar solvent, because the charge on the reactants is greater than the charge on the transition state. But there might be a solubility problem to dissolve a charged nucleophile in nonpolar solvent. Therefore, a polar aprotic solvent is used. A polar protic solvent will be used if the nucleophile is neutral. If a reactant in the rate-determining step is charged, increasing the polarity of the solvent will decrease the rate of the reaction. If none of the reactants in the rate-determining step is charged, increasing the polarity of the solvent will increase the rate of the reaction. An S N 2 reaction of an alkyl halide is favored by a high concentration of a good nucleophile in an aprotic polar solvent. An S N 1 reaction of an alkyl halide is favored by a poor nucleophile in a protic polar solvent. 8.10 Intermolecular versus Intramolecular Reactions If a molecule contains both a nucleophile and a leaving group, there are two possible S N 2 reactions: intermolecular and intramolecular 1. Intermolecular reaction: a nucleophile of one molecule displaces the leaving group of the other molecule. 2. Intramolecular reaction: a nucleophile displaces the leaving group of the same molecule (S N 2 reaction occurs in one molecule). Which reaction is more likely to occur, intermolecular reaction or intramolecular reaction? :
It depends on the concentration of the bifunctional molecule and the size of the ring that will be formed in the intramolecular reaction. 1. Intramolecular reaction is favorable at low concentration because the two functional groups have a better chance of meeting together. 2. Above argument is true when the intramolecular reaction product is 5-6 membered ring, but it is not true when the ring is too small (3-4 membered ring) or too large( over 7) because of the ring strain. 8.11 Biological Methylating Reagents have Good Leaving Group Biological systems use S-adenosylmethionine (SAM) and N 5 -methltetrahydrofolate as methylating agents.